Mutations in the gene encoding surfactant protein A2 (SP-A2) cause familial idiopathic pulmonary fibrosis (IPF) and lung cancer, both lethal diseases with limited treatment options. The molecular mechanism of mutant surfactant proteins are not well understood and underlie a spectrum of lung diseases affecting children and adults. We have recently discovered that expression of certain mutant surfactant proteins in lung epithelial cells leads to increased expression and secretion of latent TGF-?, a potent pro-fibrotic and pro-oncogenic cytokine. The specific hypothesis to be tested is that expression of mutant surfactant proteins in alveolar epithelial cells leads to pulmonary fibrosis through the autocrine and paracrine effects of TGF-?, whose secretion is induced through ER stress-dependent and ER stress-independent pathways. Our rationale for the proposed work is that it will provide enhanced understanding of the gain-of-function effects of mutant surfactant proteins in causing progressive pulmonary fibrosis. The first aim will focus on studying this mechanism in vitro by determining: Which variant surfactant proteins have a gain-of-function effect of inducing increased latent TGF-? secretion and what is the relative contribution of ER stress signaling that mediates this mechanism? The molecular mechanism of the underlying pathways will be probed using a combination of proteomic and transcriptomic approaches as well as chemical inhibitors. The second aim will define the injury or reprogramming of type II alveolar epithelial cells caused by acute or chronic expression of mutant surfactant proteins and the involvement of various pathways that affect the cellular context of TGF-? signaling. In the third and last aim, we will elucidate the in vivo molecular mechanism of mutant SP-A2 protein-mediated disease using a novel transgenic mouse model. We will specifically explore the genetic contributions of the TGF-? signaling and telomerase pathways in contributing to bleomycin-induced lung fibrosis. While the signaling pathways downstream of TGF-? are well characterized, the inciting events that lead to its expression and secretion are not. Successful completion of these aims will elucidate this novel pathway of mutant surfactant induced latent TGF-? secretion. This work will generate insight into the pathways linking protein misfolding, ER stress, EMT, cellular differentiation and proliferation in lung fibrosis and will assist in the identification of unique targets for drug development.